Abstract
Annual influenza epidemics and occasional pandemics pose a severe threat to human health. Host cell factors required for viral spread but not for cellular survival are attractive targets for novel approaches to antiviral intervention. The cleavage activation of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity. However, it is unknown which proteases activate influenza viruses in mammals. Several candidates have been identified in cell culture studies, leading to the concept that influenza viruses can employ multiple enzymes to ensure their cleavage activation in the host. Here, we show that deletion of a single HA-activating protease gene, Tmprss2, in mice inhibits spread of mono-basic H1N1 influenza viruses, including the pandemic 2009 swine influenza virus. Lung pathology was strongly reduced and mutant mice were protected from weight loss, death and impairment of lung function. Also, after infection with mono-basic H3N2 influenza A virus body weight loss and survival was less severe in Tmprss2 mutant compared to wild type mice. As expected, Tmprss2-deficient mice were not protected from viral spread and pathology after infection with multi-basic H7N7 influenza A virus. In conclusion, these results identify TMPRSS2 as a host cell factor essential for viral spread and pathogenesis of mono-basic H1N1 and H3N2 influenza A viruses.
Highlights
Annual influenza epidemics and unpredictable pandemics pose a severe threat to human health, exemplified by the estimated 30– 50 million deaths caused by the 1918 pandemic
We focused our analysis on viruses of the H1N1 and H3N2 subtypes, since viruses of these subtypes are presently circulating in the human population
We report that the deletion of a single host protease gene, Tmprss2, in mice protects the host against viral spread in infected lungs
Summary
Annual influenza epidemics and unpredictable pandemics pose a severe threat to human health, exemplified by the estimated 30– 50 million deaths caused by the 1918 pandemic. The cleavage of the influenza virus hemagglutinin (HA) by host cell proteases is essential for viral infectivity [2,3]. The HA proteins of highly pathogenic avian influenza viruses harbor multiple basic amino acids at their cleavage site and are activated by furin [4]. Low pathogenic avian and human influenza viruses contain a mono-basic cleavage site in their HA proteins. Several studies showed that multiple secreted proteases can activate human influenza viruses for infection of cell lines (see [5,6] for examples and [7] for a review). The analysis of cultured human respiratory epithelium demonstrated that influenza virus cleavage activation is a cell-associated process and no evidence for a role of secreted proteases was obtained [8]. The role of TMPRSS2 in influenza virus spread and pathogenesis in the infected host has not yet been studied
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